Compounds of the present invention modulate the activity of the chemokine CCR5 receptors. The CCR5 receptor is a member of a subset of a large family chemokine receptors characterized structurally by two adjacent cysteine residues. Human chemokines include approximately 50 small proteins of 50-120 amino acids that are structurally homologous. (M. Baggiolini et al., Ann. Rev. Immunol. 1997 15:675-705) The chemokines are pro-inflammatory peptides (reviewed in Luster, New Eng. J. Med. 1998 338:436-445 and Rollins, Blood 1997 90:909-928). The name “chemokine” is a contraction of “chemotactic cytokines”. The chemokines are a family of leukocyte chemotactic proteins that are released by a wide variety of cells such as macrophages, monocytes, eosinophils, neutrophiles, fibroblasts, vascular endothelial cells, smooth muscle cells, and mast cells, at inflammatory sites and attract leukocytes to various tissues, which is an essential response to inflammation and infection. Chemokines can be grouped into two subfamilies, based on whether the two amino terminal cysteine residues are immediately adjacent (CC family) or separated by one amino acid (CXC family). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES (CCL5), MIP-1α (CCL3, macrophage inflammatory protein), MIP-1β (CCL4), the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. Naturally occurring chemokines which can stimulate the CCR5 receptor include MIP-1α, MIP-1β and RANTES.
Accordingly, drugs which inhibit the binding of chemokines such as MIP-1α, MIP-1β and RANTES to these receptors, e.g., chemokine receptor antagonists, may be useful as pharmaceutical agents which inhibit the action of chemokines such as MIP-1α, MIP-1β and RANTES on the target cells. The identification of compounds that modulate the function of CCR5 represents an excellent drug design approach to the development of pharmacological agents for the treatment of inflammatory conditions and diseases associated with CCR5 receptor.
The pharmacokinetic challenges associated with large molecules, proteins and peptides resulted in the establishment of programs to identify low molecular weight antagonists of CCR5. The efforts to identify chemokine modulators have been reviewed. (W. Kazmierski et al. Biorg Med. Chem. 2003 11:2663-76; L. Agrawal and G. Alkhatib, Expert Opin. Ther. Targets 2001 5(3):303-326; Chemokine CCR5 antagonists incorporating 4-aminopiperidine scaffold, Expert Opin. Ther. Patents 2003 13(9):1469-1473; M. A. Cascieri and M. S. Springer, Curr. Opin. Chem. Biol. 2000 4:420-426, and references cited therein)
Low Molecular-Weight CCR5 Antagonists
Takeda's identified TAK-779 as a potential CCR5 antagonist. (M. Shiraishi et al., J. Med. Chem. 2000 43(10):2049-2063; M. Babba et al. Proc. Nat. Acad. Sci. USA 1999 96:5698-5703) and TAK-220 (C. Tremblay et al. Antimicrob. Agents Chemother. 2005 49(8):3483-3485).
WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.) disclose heterocyclic compounds that are potent and selective CCR5 antagonists. Pfizer's UK427,857 (MVC) has been approved by the FDA for treating HIV-1. (P. Dorr et al., Antimicrob. Agents Chemother. 2005 49(11):4721-4732; A. Wood and D. Armour, Prog. Med. Chem. 2005 43:239-271; C. Watson et al., Mol. Pharm. 2005 67(4):1268-1282; M. J. Macartney et al., 43rd Intersci. Conf. Antimicrob. Agents Chemother. Sep. 14-17, 2003, Abstract H-875)
Schering has advanced Sch-351125 (SCH-C) into Phase I/II clinical studies and reported the advance of a more potent follow-up compound, Sch-417690 (SCH-D) into Phase I studies. (S. W. McCrombie et al., WO00066559; B. M. Baroudy et al. WO00066558; A. Palani et al., J. Med. Chem. 2001 44(21):3339-3342; J. R. Tagat et al., J. Med. Chem. 2001 44(21):3343-3346; J. A. Esté, Cur. Opin. Invest. Drugs 2002 3(3):379-383; J. M. Struzki et al. Proc. Nat. Acad. Sci. USA 2001 98:12718-12723).
Merck has disclosed the preparation of (2S)-2-(3-chlorophenyl)-1-N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzothiophene-3,4′-piperidin-1′-yl)butane S-oxide (1) and related derivatives, trisubstituted pyrrolidines 2 and substituted piperidines 3 with good affinity for the CCR5 receptor and potent-HIV-1 activity. (P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:265-270; P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:2469-2475; P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:2475-2479; J. J. Hale et al., Bioorg. Med. Chem. Lett., 2001 11:2741-22745; D. Kim et al., Bioorg. Med. Chem. Lett., 2001 11:3099-3102) C. L. Lynch et al. Org. Lett. 2003 5:2473-2475; R. S. Veazey et al. J. Exp. Med. 2003198:1551-1562.
ONO-4128, E-913, AK-602 was identified in a program initiated at Kumamoto University (K. Maeda et al. J. Biol. Chem. 2001 276:35194-35200; H. Nakata et al. J. Virol. 2005 79(4):2087-2096)
In WO00/166525; WO00/187839; WO02/076948; WO02/076948; WO02/079156, WO2002070749, WO2003080574, WO2003042178, WO2004056773, WO2004018425 Astra Zeneca disclose 4-amino piperidine compounds which are CCR5 antagonists.
EP1236726 (H. Habashita et al.) discloses triazaspiro[5.5]undecane derivatives exemplified by AK602 which modulate the cytokine receptors. The compounds fall outside the scope of the current invention. (H. Nakata et al. Poster 546a, 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif., Feb. 8-11, 2004; other analogs have also been disclosed, see, e.g. K. Maeda et al., J. Biol. Chem. 2001 276(37): 35194-35200)
The aforementioned compounds fall outside the scope of the present invention.
In U.S. Patent Publication 20050176703 published Aug. 11, 2005 S. D. Gabriel et al. disclosed 1-oxa-3,8-diaza-spiro[4.5]decan-2-one and 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one derivatives which are CCR5 receptor antagonists.